Managing Patients With Cutaneous Squamous Cell Carcinoma

Shannon Trotter, DO, FAOCD, FAAD, DOCS Dermatology, Canal Winchester, Ohio, discusses the diagnostic and therapeutic challenges with cutaneous squamous cell carcinoma (cSCC). Dr Trotter highlights the difficulties associated with risk stratification, the importance of multidisciplinary collaboration, and the use of gene expression profiling.

Dr Trotter concluded, “The goal of our paper was really to bring all the challenges that surround [cSCC] together to really hopefully have that stronger, multidisciplinary approach where we can develop a better consensus on how we’re going to approach that patient. And as [cSCC] gets the time and attention it deserves, I do truly believe it will result in more effective treatment strategies and outcomes for patients.”

Transcript:

I am Dr. Shannon Trotter, board certified dermatologist. I practice in the Columbus, Ohio area with DOCS Dermatology.

How do you approach the decision of referring a patient for radiation or systemic therapy, or surgery?

As a dermatologist, we often make referrals for our cutaneous squamous cell carcinoma patients, particularly for head and neck. We are often referring first to our Mohs surgeons and working with them for surgical clearance of the tumor. Now myself, when I look to refer to radiation oncology, I'm looking at T3/T4 tumors, cutaneous squamous cell carcinomas that have high-risk features like perineural invasion. And then more recently, I've utilized gene expression profiling to help aid in my decision to refer, and particularly in regards to radiation oncology.

Sometimes when I've done the biopsy, I simply made the referral to my Mohs surgeon, and it's actually considered a low-risk tumor on initial biopsy, and because of that heterogeneity or subclinical spread, once they go in for the surgery, the Mohs surgeon may find that the tumor is much more extensive. And now they've actually changed from being a low-risk squamous cell to a high-risk squamous cell carcinoma.

And then collaboratively, I'm usually working with my Mohs surgeon to make those referrals, which again may include radiation oncology, potentially surgical oncology as well, especially for those that have deeper or wider spread. And then we're including medical oncology too, with addition of imaging and potential for systemic therapy.

What is the role of multidisciplinary collaboration when managing patients with cSCC?

The role of multidisciplinary care is essential in the United States. Some sources will estimate that essentially cutaneous squamous cell carcinoma deaths are estimated to be around 15,000, which far exceeds that of melanoma. So when I look at cutaneous squamous cell carcinoma, it is a much more complex disease than I think what we appreciate and it really deserves attention and awareness regarding its diagnostic challenges, therapeutic and management limitations that we have.

Including our colleagues that are in the surgical realm of surgical oncology, medical oncology, and radiation oncology are very important. That approach gives us a more comprehensive view, especially for those more complex cases that we're really not confident in the right direction we need to go for treatment. It allows everyone to give input based on, yes, guidelines, but also based on clinical experience and gestalt because there is value in that and how we may manage these patients. And that can vary per institution or again, based on just personal clinical experience of the clinician.

What is your perspective on gene expression profiling?

Gene expression profiling can be a useful tool to help stratify patients further based on just their tumor biology. And I think this is where cancer care has been headed in the future, and we see this for other cancers like breast cancer.

Now there is a commercially-available test, the 40-GEP test, it's available and it can help identify patients with cutaneous squamous cell carcinoma as low higher risk or highest risk. And this is something that I think can help assist us where there are some inconsistencies with our staging systems. First, as I mentioned before, people may use one staging system over the other, or maybe they use a guideline with the NCCN, and then some people sort of use a combination thereof, but none of those systems actually include looking at tumor biology or gene expression profiling. Adding that in can kind of help us assess a cutaneous squamous cell carcinoma where our staging systems are currently limited. And we know based on our current staging systems, there are patients that are diagnosed or designated as low risk that go on to metastasize, and the converse is true too. We have patients that are designated high risk that don't go on to metastasize. I think gene expression profiling to a degree can help split that difference and it can help then guide and inform further treatment decisions and management for the patient.

Now in particular, there is a study that looked at the 40-GEP test and the use of adjuvant radiation therapy. It actually showed patients that received the 40-GEP test and had a class 2B, or that highest risk result, who received adjuvant radiation therapy had a 50% lower rate of metastasis than those who did not receive adjuvant radiation therapy. And in essence, what this means is that the test actually helped predict which patients would benefit most from the treatment.

In the dermatology space, we can sometimes be overly or hypercritical, I think, of radiation therapy. I think it's a bias inherently in our discipline. Having directed tests to identify those patients that we think should go on to receive that therapy, and to help inform that conversation further with radiation oncology would be very helpful. And I think this is where GEP can really play a role. It's powerful information to really help decide what potentially should be the next step. And it doesn't mean we don't follow guidelines, we follow guidelines, but then you add this additional information of gene expression profiling to assist in that conversation. And that's something that typically we would have the patient undergo with a radiation oncologist as well.

I do think GEP is something that needs some additional research and information on how we're going to utilize it going into the future for other clinical applications for cutaneous squamous cell carcinoma, especially if you think about the role that it might serve for helping with identifying patients who maybe are high risk but might benefit from routine imaging. And then maybe in the future it might be helpful in predicting those that benefit from various systemic therapies that are designed to go after cutaneous squamous cell carcinoma.

What are the special considerations needed for patients with head and neck cSCC?

Head and neck cutaneous squamous cell carcinomas are high risk by definition, just based on location. And we know that they basically comprise the majority of all cutaneous squamous cell carcinomas that we see. The majority of head and neck cases can’t typically be cured with surgical resection alone. But once you have a metastatic head and neck case, that 5-year survival rate is decreased by 50%, once metastasis has occurred. So, we know this area is high risk, now we know it's because of location. It has high-risk potential metastasis and recurrence.

And then also you have to think about just where it's at, right? If it's on the head and neck, there's going to be impact on both the functional aspect of the body, especially if it's located near the eyelid, on the nose, the ear, the lip, And, of course there are cosmetic outcomes which also play a role in our decision-making. Head and neck definitely deserves that extra attention, mostly because of, yes, the high mortality associated with it once metastasis has occurred, but also because of this other reasons including functional and cosmetic outcomes.

What do you see as the future of treatment for patients with cSCC?

The future of cutaneous squamous cell carcinoma is definitely, I believe, bright. We're drawing more attention to cutaneous squamous cell carcinoma and not just lumping it under the umbrella of non-melanoma skin cancer. Often people think of squamous cell carcinoma and basal cell carcinoma, especially in dermatology, on an equal playing field. And now people are recognizing that there are high-risk patients that develop cutaneous squamous cell carcinoma that goes on to metastasize. And with that recognition comes more attention to the fact that we have to identify those patients that are high risk.

So where do we think this is going to go? I think that you're definitely going to see a more prominent role for gene expression profiling and potentially other biomarkers to identify those high-risk patients. Those high-risk patients will be treated differently. And you're seeing this happen right now where potentially they're undergoing imaging before symptoms have actually occurred. And there are also systemic therapies available, especially that target the immune system that we believe will be helpful for maybe some of those patients even preemptively before we've seen metastatic disease. Now, while we don't have studies to support that at this time, I think that's where you're going to see future directions go. Are we going to be able to identify high risk patients early on, potentially offer them therapy and have an impact on overall survival for those patients as well.

In addition, I think that GEP may be helpful, why we use it now, for predicting response to radiation therapy, maybe other systemic therapies that might play a role in that regard. And again, additional studies are needed to validate that if that's actually true. And if you look at intralesional therapy, there are clinical trials looking at intralesional therapy now for cutaneous squamous cell carcinomas, primary treatment, and also neoadjuvant treatment and potentially adjuvantly as well. I do think there's a call for this to go after skin cancer. In general, we've seen this trend in dermatology to look beyond just surgical means if possible. And what are the role other modalities to treat skin cancers as well.

When I look at cutaneous squamous cell carcinoma, I love the fact that it's getting the attention it deserves. The goal of our paper was really to bring all the challenges that surround it together to really hopefully have that stronger multidisciplinary approach where we can develop a better consensus on how we're going to approach that patient. And as it gets the time and attention it deserves, I do truly believe it'll result in more effective treatment strategies and outcomes for patients.

Source:

Beach SC, Cusick AS, Farberg AS, and Trotter SC. A comprehensive narrative review of the challenges surrounding cutaneous SCC. Dermatol Ther. Published on: June 23, 2025. doi: 10.1007/s13555-025-01470-7.

Arron ST, Cañueto J, Siegel J, et al. Association of a 40-gene expression profile with risk of metastatic disease progression of cutaneous squamous cell carcinoma and specification of benefit of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys. Published on: May 27, 2024. doi: 10.1016/j.ijrobp.2024.05.022.